Abstract:

Alzheimer’s disease (AD), the most common human neurodegenerative disease, is characterized pathologically
by numerous deposits of amyloid plaques in the brain. Systemic administration of clioquinol (CQ) and inoculation with
amyloid-beta42 (Aβ42) vaccines have been demonstrated to significantly inhibit deposits of amyloid in AD brains. However,
each of these treatments has also been reported to be neurotoxic. The generation of transgenic mice models of AD
has made it possible to study aspects of this disease employing experimental animals. In the present study, we investigated
the efficacy and toxicity of CQ and Aβ42 vaccine in a transgenic AD (APP/PS1) mouse model. Our results confirmed that
both CQ and Aβ42 vaccine were effective in significantly reducing the deposits of amyloid in the brains of transgenic AD
mice. We also report here that systemic CQ induces myelinopathies in the dorsal lateral geniculate nucleus (DLG), which
was almost devoid of amyloid plaques and is the primary site of retinal efferent projections via the optic nerve. This is the
first report that systemic administration of CQ causes myelinopathies in the central nervous system (CNS) of a transgenic
AD mouse model as well as wild-type mice. Inoculation with an Aβ42 vaccine was also found, for the first time, to result
in a significant increase in plaque-independent astrocytic hyperplasia in the dorsal part of the lateral septal nucleus (LSD)
which was also devoid of plaques, reflecting potential brain inflammatory processes.

Abstract:Alzheimer’s disease (AD), the most common human neurodegenerative disease, is characterized pathologically
by numerous deposits of amyloid plaques in the brain. Systemic administration of clioquinol (CQ) and inoculation with
amyloid-beta42 (Aβ42) vaccines have been demonstrated to significantly inhibit deposits of amyloid in AD brains. However,
each of these treatments has also been reported to be neurotoxic. The generation of transgenic mice models of AD
has made it possible to study aspects of this disease employing experimental animals. In the present study, we investigated
the efficacy and toxicity of CQ and Aβ42 vaccine in a transgenic AD (APP/PS1) mouse model. Our results confirmed that
both CQ and Aβ42 vaccine were effective in significantly reducing the deposits of amyloid in the brains of transgenic AD
mice. We also report here that systemic CQ induces myelinopathies in the dorsal lateral geniculate nucleus (DLG), which
was almost devoid of amyloid plaques and is the primary site of retinal efferent projections via the optic nerve. This is the
first report that systemic administration of CQ causes myelinopathies in the central nervous system (CNS) of a transgenic
AD mouse model as well as wild-type mice. Inoculation with an Aβ42 vaccine was also found, for the first time, to result
in a significant increase in plaque-independent astrocytic hyperplasia in the dorsal part of the lateral septal nucleus (LSD)
which was also devoid of plaques, reflecting potential brain inflammatory processes.